Exploring low clozapine C/D ratios, inverted clozapine-norclozapine ratios and undetectable concentrations as measures of non-adherence in clozapine patients

Concomitant Use of Clozapine and Suvorexant Associated With Doubling of Clozapine Plasma Levels: A Case Report

“…First, we must interpret the findings with caution because this patient's mean C/D ratio of 1.33 when she was not taking suvorexant was lower than the typical C/D ratio of approximately 2 for nonsmoking Asian women 5 . The possibility of nonadherence should be considered when the C/D ratio is low 12 . Although the possibility of nonadherence in this patient cannot be completely ruled out, the fact that adherence was confirmed by nurses in the inpatient setting and the gradual decline in the C/D ratio after suvorexant discontinuation suggest that nonadherence alone cannot explain the course of this case.…”

A Systematic Review of Clozapine Concentration–Dose Ratio from Therapeutic Drug Monitoring Studies in Children and Adolescents Treated with Clozapine for Mental Disorders

“…Therefore, at least 5 days (5 half-lives) from the last dosage change are required in most patients to achieve a steady state, but 10 days may be required in patients who are clozapine PMs. 33 Based on the short half-life proposed by the clozapine package insert, most published articles define trough time as at least 12 hours from the last dose. In 46 adults with schizophrenia, Jakobsen et al 34 found that the impact of deviations in clozapine TDM sampling time within the period of 10-14 hours postdose appeared to be of minor importance when looking at median percentage differences.…”

“…Thus, the relationship between clozapine dose and concentration can be represented by the C/D ratio, 36 which is stable in an individual as long as 2 conditions are met: (1) the absence of changes in clozapine metabolism-inducing or clozapine metabolism-inhibiting factors and (2) clozapine concentrations higher than 150 ng/mL. 33 Clozapine C/D ratios from trough steady-state concentrations in the range of linear kinetics are a good measure of clozapine clearance. As clozapine follows linear kinetics: (1) the relationship between clozapine concentration and dose is linear, and (2) the clozapine C/D ratio is constant in the same individual as long as the variables that influence clozapine clearance remain unchanged.…”

“…A much more frequent cause of very low clozapine C/D ratios is nonadherence, which is very frequent and may occur in at least one-third of outpatients treated with clozapine. 33 Partial nonadherence usually manifests as a low clozapine C/D ratio for the corresponding clozapine dose. The clozapine-to-norclozapine ratio is calculated by dividing the plasma clozapine concentration by the norclozapine concentration; in a systematic review of 2317 adult patients across 19 studies, the weighted mean of the C/D ratio was 1.73 but the range varied widely from 1.19 to 3.37.…”

“…25 An inverted clozapine-to-norclozapine ratio, meaning a ratio of ,1 in the case where plasma concentration of norclozapine is higher than that of clozapine, is another sign of partial nonadherence as long as the concentration is collected at trough and steady state, and the doses provide plasma concentrations higher than 150 ng/mL. 33,35 Nondetectable concentrations of clozapine and even more of norclozapine are a sign of full nonadherence. Different laboratories have different limits for nondetectable concentrations, but clozapine concentrations may take up to 7-9 days to go from a therapeutic to a nondetectable concentration, whereas in the same patient, norclozapine concentrations would take 12-14 days to become undetectable.…”